2.1. Aminothiol Compounds
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyol®, NSC 296961, and WR-2721 and which will hereinafter be referred to as “amifostine”) and other aminothiol compounds are disclosed in U.S. Pat. No. 3,892,824 to Piper et al. These compounds were originally developed as antiradiation agents (radio-protectants), in particular to be used prior to exposure to x-ray or nuclear radiation, to protect against the harmful effects of such exposure which may be encountered during military conflicts.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant, i.e., as a protectant administered prior to therapy to reduce the undesirable adverse effects which arise during the use of chemotherapy and radiation therapy in the treatment of cancer. Nygaard et al., eds., 1983, Radioprotectors and Anticarcinogens, Academic Press, Inc., New York, pp. 73–85; Grdina et al., 1985, “Radioprotector WR-1065 Reduces Radiation-Induced Mutations of the HGPRT Locus in V79 Cells,” Carcinogenesis (London) 6:929–931. In addition, these compounds have been reported to afford protection against the adverse effects of chemotherapeutic agents, for example, alkylating agents such as cisplatin and carboplatin, when administered before or concurrently with the chemotherapeutic agent. Jordan et al., 1982, “Modulation of cis-platinum renal toxicity by the Radioprotective agent WR-2721”, Exp. Mol. Pathol. 36:297; Doz et al., 1991, “Experimental Basis for Increasing the Therapeutic Index of Carboplatin in Brain Tumor Therapy by Pretreatment With WR-Compounds”, Cancer Chemother. Pharmacol. 28:308. Similarly, it has been reported that amifostine has been used experimentally prior to therapy to protect HIV-infected patients (AIDS) from the harmful side effects of 3′-azido-3′-deoxythymidine (AZT) therapy. International Published Application WO 90/14007, published Nov. 29, 1990. Amifostine and its derivatives have been shown to exert these reported protective effects without affecting the beneficial properties of the administered therapeutic agents. This is, in the case of chemotherapy, believed to be due to the selective uptake of the protective thiol and other metabolites into normal tissue. Yuhas, 1980, “Active versus Passive Absorption Kinetics as the basis for Selective Protection of Normal Tissues by WR-2721”, Cancer Res. 40:1519–1524; Yuhas, 1979, “Differential Protection of Normal and Malignant Tissues Against the Cytotoxic Effects of Mechlorethamine” Cancer Treat. Rep. 63:971–976.
Amifostine and related aminothiol compounds have also been shown to stimulate bone marrow growth. See U.S. patent application Ser. No. 08/390,713; International Published Application WO 96/25045 published Aug. 22, 1996; List et al., “Amifostine Stimulated Formation of Multipotent Progenitor and Generated Macroscopic Colonies in Normal and Myelodysplastic Bone Marrow,” Proc. Am. Soc. Clin. Oncol. 15:449 [1403] [Abstract]. Currently, amifostine is in Phase II clinical trials as a bone marrow stimulant in patients suffering from myelodysplastic syndrome. List et al., 1996, “Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial,” Am. J. Hem. 1 (Abstract); List et al., 1996, “Amifostine Promotes in vitro and in vivo Hematopoiesis in Myelodysplastic Syndromes,” Chem. Found Sympos. (Abstract); List et al., 1996, “Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial,” Abstract, 8th Annual Meeting, American Society of Hematology, Orlando, Fla. Pre-exposure with aminothiol compounds is capable of causing the bone marrow function to more rapidly recover following chemotherapy. List et al., 1996, “Amifostine Protects Primitive Hematopoietic Progenitors Against Chemotherapy Cytotoxicity,” Semin. Oncol. 23 (4) Supp. 8:58–63.
Presently, amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer. Physicians' Desk Reference, 51st ed. 1997, p. 485–486. The recommended starting dosage for adults in an FDA-approved indication is 910 mg/m2 administered once daily as a 15-minute intravenous (i.v.) infusion, starting 30 minutes prior to chemotherapy. However, clinical trials have used doses as low as 100 mg.
U.S. Pat. Nos. 5,567,686 and 5,488,042, both to Grdina, allege that the administration of an aminothiol compound before irradiation of a mammal affords protection against genotoxic mutagenesis. Although the 5,488,042 patent discloses administering an aminothiol up to about three hours after irradiation, both patents focus solely on prevention of mutations, rather than the treatment or reversal of radiation- or chemotherapy-induced damage. Further, the Grdina patents are silent as to the use of any aminothiol compound in humans to treat chemotherapy- or radiation-induced disorders and toxicities including neuro-, nephro-, hematological or mucosal disorders.
Nagy et al., 1986, “Protection Against cis-Diamminedichloroplatinum Cytotoxicity and Mutagenicity in V79 Cells by 2-[(Aminopropyl)amino]ethanthiol,” Cancer Research 46:1132–1135, disclose that the free thiol metabolite of amifostine, also known as WR-1065, protects against cytotoxicity in V79-B310H Chinese hamster cells when administered before, during and immediately after treatment of the cells with cis-diamminedichloroplatinum (cis-DDP, “cisplatin”). Although some protection against cell death was observed under all conditions, Nagy et al. report that maximum protection was obtained when WR-1065 was present in the cell growth medium for 30 minutes prior to exposure of cells to cisplatin. In addition, Nagy et al. state that little if any difference in the magnitude of protection against cell killing was seen whether the WR-1065 was present either during or immediately following cisplatin exposure.
Treskes et al., 1992, “Effects of the Modulating Agent WR-2721 and its Main Metabolites on the Formation and Stability of Cisplatin-DNA Adducts in Vitro in Comparison to the Effects of Thiosulphate and Diethyldithiocarbonate,” Biochemical Pharmacology 43(5):1013–1019 investigated the ability of amifostine and its main metabolites, WR-1065 and WR-33278, to prevent formation of adducts of cisplatin with the DNA of salmon sperm. They found that amifostine, WR-1065 and WR-33278 caused a decrease in the platination of salmon sperm in vitro when the compounds were present concomitantly with cisplatin. It was also observed that part of the already formed cisplatin-DNA adducts is disrupted during post-incubation with subject compounds, but this decrease in adduct levels was small compared to those obtained during co-incubations. Treskes et al. speculated that conformational changes in DNA induced by the WR-1065 metabolite of amifostine observed by other researchers might provide a rational for applying amifostine after cisplatin administration.
However, Treskes et al. later reported in 1993, “WR2721 as a Modulator of Cisplatin- and Carboplatin-induced Side Effects in Comparison with Other Chemoprotective Agents: A Molecular Approach,” Cancer Chemother. Pharmacol. 33:93–106, that neither WR-1065 nor WR-2721 (amifostine) could protect cells from the cytostatic effect of cisplatin when the compounds were incubated with cells one hour after cisplatin exposure. Further, it was found that amifostine given 30 minutes after cisplatin did not protect mice at all from nephrotoxicity. Treskes et al. concluded that the selective protection of multiple non-tumor tissue by WR-1065 from cisplatin-induced toxicity is explained by a strong prevention, not reversal, of cisplatin-induced cellular damage. Treskes et al. further observed that these findings were in agreement with the hypothesis that the prevention of damage is the main mechanism of protection and that reversal of platinum-induced damage is not an important mechanism of protection.
Nephrotoxicity, produced by drugs such as cisplatin, has important consequences for the patient, with potential permanent loss of 50% or more of normal renal function (Kemp, et al. J. Clin. Oncoloqy, 14:2101–2112, July, 1996). This can produce serious disability, requiring the need for dialysis in severe cases, and early mortality. It also has important consequences for the ability of the patient to be safely treated with other forms of life-sustaining chemotherapy and other medications such as antibiotics that are themselves renally toxic or require adequate renal function for elimination from the body.
Neurotoxicity may significantly decrease a patient's quality of life because of loss or distortion of sensation in the fingers, toes, hands and feet, as well as loss of fine muscle movements, resulting in the inability to perform routine functions such as buttoning of clothes. In more severe cases, patients suffer loss of sufficient motor function so that they require walkers or wheelchairs.
2.2. Cisplatin- and Paclitaxel-Induced Toxicities
Cisplatin continues to be an agent of choice for the treatment of advanced ovarian cancer, testicular cancer, bladder cancer and head, neck and lung cancers. McGuire et al., 1996, “Cyclophosphamide and cisplatin compared with Paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer,” N. Engl. J. Med. 334:1–6. However, the cytotoxic effects of cisplatin on normal tissue, including the kidneys, can result in long-term debilitating effects which may limit the ability to deliver therapeutic doses against the cancer. Despite aggressive hydration and administration of mannitol, cisplatin-induced nephrotoxicity remains a significant cause of morbidity and mortality. Finley et al., 1985, “Cisplatin nephrotoxicity: A Summary of Preventative Interventions,” Drug Intell. Clin. Pharm. 19:362–367; Kemp et al., 1996, “Amifostine Pretreatment of Protection Against Cyclophosamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer,” J. Clin. Oncol. 14:2101–2112; Stewart et al., “Association of Cisplatin Nephrotoxicity with patient Characteristics and Cisplatin Administration Methods,” Cancer Chemother. Pharmacol. 40:293–308.
Even when protective agents are administered prior to or during cisplatin treatment, toxicities may still be observed. The cumulative cisplatin nephro-toxicity that occurs can be treatment-limiting, precluding further administration of cisplatin and the ability to administer effective doses of renally-excreted second-line chemotherapy Kemp et al., 1996, J. Clin. Oncol. 14:2101–2112. In addition, drug therapy for other conditions can be affected, either because the agents are renally excreted, or because of their intrinsic potential to worsen renal function. Nephrotoxicity is also associated with other platinum coordination complexes such as carboplatin which are also used to treat cancers.
The nephrotoxicity associated with cisplatin is cumulative, i.e., incremental damage occurs with repeated courses of therapy. Daugaard et al., 1989, “Cisplatin nephrotoxicity,” Cancer Chemother. Pharmacol. 21:1; du Bois, et al., 1994, “Cisplatin and carboplatin induced acute, cumulative and chronic nephrotoxicity,” Proc. Annu. Meet. Am. Assoc. Cancer Res. 35: A1475. Loss of renal function occurring secondary to cisplatin is typically permanent. Macleod et al., 1988, “The effect of cisplatin on renal function in patients with testicular tumors,” Clin. Radiol. 39: 190–192; Aass et al., 1990, “Renal function related to different treatment modalities for malignant germ cell tumors,” Br. J. Cancer 62:842–846; Meijer, et al., 1983, “Influence of combination chemotherapy with cisdiammine chloroplatinum on renal function: Long term effects,” Oncology 40:170–173. Risk factors for development of this toxic effect include age, a history of renal irradiation, dehydration, and alcoholism. Anand et al., 1993, “Newer insights into cisplatin nephrotoxicity,” Ann. Pharmacother. 27:1519–1525.
Nephrotoxicity associated with administration of cisplatin and other platinum coordination complexes is generally observed during the second week after a dose and is manifested by elevations in BUN and/or serum creatinine and/or a decrease in creatinine clearance or serum magnesium. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Nephrotoxicity may be accentuated in patients with pre-existing risk factors such as diabetes or hypertension as well as individuals who are receiving other nephrotoxins such as aminoglycoside antibiotics or antifungals such as amphoterecin. Options available to reduce cumulative cisplatin renal toxicity are limited, and generally involve reducing its dosage or frequency of administration, both of which risk a potential reduction in antitumor effectiveness. Kemp et al., 1996, J. Clin. Oncol. 14:2101–2112. Pretreatment or simultaneous administration of amifostine is also an option, but these treatments are not always effective.
In addition to nephrotoxicity, many other toxicities are associated with the administration of platinum coordination compounds. For example, ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin (50 mg/m2) and is manifested by tinnitus and/or hearing loss in the high frequency range (4000–8000 Hz). Decreased ability to hear normal conversational tones may occur occasionally. Deafness after the initial dose of cisplatin has been reported rarely. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses. In addition, myelosuppression occurs in 25–30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 with most patients recovering by day 39. Leukopenia and thrombocytopenia are observed at higher doses (>50 mg/m2).
Neurotoxicity, usually characterized by peripheral neuropathies, is also associated with administration of platinum coordination complexes. The neuropathies, in the form of loss or distortion of sensation, or loss of fine motor function, usually occur after prolonged therapy (4–7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin-induced neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of the platinum coordination complex. Generally, in the event of cisplatin-induced neuropathic symptoms, cisplatin is discontinued until the symptoms subside or disappear. The neuropathy, however, may progress even after treatment is stopped. Some preliminary evidence suggests that neuropathy may be irreversible in some patients. Lhermitte's sign, dorsal column myelopathy, autonomic neuropathy, loss of taste and seizures have also been reported. Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, or loss of sufficient motor function so that a patient requires a walker or wheel chair for movement, have been reported and are usually associated in patients receiving a relatively high cumulative dose of cisplatin and exhibiting advanced symptomatic stages of peripheral neuropathy. Amifostine has demonstrated the ability to reduce the incidence of neuropathies when administered prior to cisplatin. In a prospective evaluation of patients treated with cisplatin regimens±amifostine at the Hospital of the University of Pennsylvania Cancer Center, patients pretreated with amifostine had a significantly lower incidence of cisplatin neuropathies and the onset of neuropathies occurred at a significantly higher cumulative dose of cisplatin [Mollman J E, Glover D J, Hogan W M, Furman R E: Cisplatin neuropathy: Risk factors, prognosis and protection by WR-2721. Cancer 61:2192–2195, 1988]. The ability of amifostine pretreatment to significantly reduce the occurrence and severity of cisplatin neuropathy was confirmed in a randomized controlled trial of cisplatin and cyclophosphamide±amifostine in women with advanced ovarian cancer [Kemp G, Rose P, Lurain J et al.: Amifostine pretreatment for protection against cyclophosphamide and cisplatin induced toxicities: Results of a randomized control trial in patients with advanced ovarian cancer. J. Clin. Oncol. 14:2101–2112, 1996].
Paclitaxel is indicated, after failure of first-line or subsequent chemotherapy, for the treatment of metastatic carcinoma of the ovary. Paclitaxel is also indicated for the treatment of breast cancer after failure of combination therapy for metastatic disease or relapse within six months of adjuvant therapy. Paclitaxel is known to have the following adverse effects: neutropenia, leukopenia, peripheral neuropathy, and arthralgia/myalgias and other neurological manifestations. The results of a clinical trial of amifostine and escalating doses of paclitaxel, indicated that pretreatment with amifostine allowed both higher single doses and cumulative doses of paclitaxel to be administered without the occurrence of dose limiting neuropathies and arthralgias/myalgias [DiPaolo R et al.: Amifostine and dose intense paclitaxel in patients with advanced malignancies. Cancer Therapeutics, Proc. Am. Soc. Clin. Oncology Vol. 16 (Abstract 826) 235a (1997)]. These may be accentuated when the drug is combined with other neurotoxic agents such as cisplatin. Many patients receiving paclitaxel also experience hypotension, asymptomatic bradycardia, and occasional episodes of silent ventricular tachycardia.
Hence, there is a need for a chemical agent for treating symptoms of neurotoxicity and nephrotoxicity which result from the administration of certain therapeutic agents, particularly, chemotherapeutics, radiation therapy, or disease states such as diabetes.